The candidate is an M.D./Ph.D. who completed clinical training in dermatology in June 1997. He is now pursuing basic research with the goal of a career as an independent investigator. The research is being carried out under the sponsorship of Dr. Stuart Schreiber in the Department of Chemistry and Chemical Biology at Harvard University. The Schreiber group has a major focus on understanding and controlling the cell cycle using genetic and biochemical approaches. DNA damage by solar ultraviolet (UV) radiation is the major cause of skin cancer, the most common type of cancer in the US. A cellular "UV response" involving activation of the p53 tumor suppressor protein has evolved to protect the genome against this solar threat. An intact response leads to cell cycle arrest and allows DNA to be repaired prior to replication preventing the permanent incorporation of mutations. Roughly 90% of squamous cell carcinomas cell carcinomas lack this UV response indicating the essential function of the pathway in protecting the genome from UV carcinogenesis. Despite the importance of this protective pathway, it is not known how DNA damage by UV leads to p53 induction. A gene called ATR has been cloned in the Schreiber group and appears likely to be the mediator of the UV-p53 response based on preliminary data. ATR belongs to a newly described family of proteins called the PIK-related kinases (phosphatidyl inositol kinase-related kinases), which mediate cell cycle arrest after cellular stresses such as DNA damage. Molecular and biochemical approaches will be used to test the hypotheses that ATR or another PIK-related kinase is required for the UV response. Endogenous ATR function will be inhibited with a dominant negative ATR allele expressed in an inducible or retroviral system. The role of ATR will then be examined in individual aspects of the response to UV-DNA damage. Later studies will focus on other proteins in this pathway including putative substrates for the UV-responsive protein. This project will update and expand the candidate's molecular and cellular biology experience and train him in the field of cell cycle regulation, facilitating future independent work in cancer biology. Scientifically it aims to provide insight into UV carcinogenesis and may suggest approaches for the prevention and treatment of skin cancer and cancer more generally.